HOW DEXAMETHASONE WORK ON COVID-19?
Introduction
Dexamethasone is a synthetic corticosteroid with predominant glucocorticoid nature (having no mineralocorticoid activity). Corticosteroids are hormones that are naturally produced from adrenal glands under stress conditions to help prepare the body for fight or flight responses. Dexamethasone was first developed in 1957 to find corticosteroidal drugs having a longer duration of action. It is an anti-inflammatory and immunosuppressive agent. Nowadays it is widely used in clinical practice for different medical conditions. It is used in arthritis, meningitis, cerebral edema, adrenal insufficiency, asthma, respiratory distress syndrome, prevention of postoperative nausea and vomiting. It is also used to counteract the side effects of tumor therapy. Recently, WHO also announced the effectivity of dexamethasone for chronic COVID-19 infections.
Mechanism of action
Glucocorticoids being lipophilic cross cell membrane and bind an intracellular receptor called glucocorticoid receptor to form glucocorticoid steroid receptor complex. Glucocorticoid receptors are associated with heat shock proteins and immunophilins. Upon binding, these proteins dissociate from the glucocorticoid steroid receptor complex and the activated complex translocates into the nucleus. In the nucleus, it binds to specific DNA sequences called DNA responsive elements and modifies transcription of target genes in either up or down-regulation. Messenger RNA formed then leaves the nucleus and direct synthesis of various proteins that elicit biological responses.
Glucocorticosteroids increase the production of anti-inflammatory compounds e.g nitro oxide synthase and inhibit the production of pro-inflammatory compounds like cytokines, adhesion molecules, chemokines, and Phospholipase A2.
Its effect includes increased gluconeogenesis, fat redistribution hyperglycemia, lymphopenia, and neutrophilia. It also increases apoptosis of monocytes, T- cells, eosinophils, and thrombocytes which leads to suppression of immunity.
Possible Mechanism of action of Covid-19
In any infection, the immune system is necessary to combat pathogen but some infections are immunomodulatory. In patients of COVID-19 immune responses are supposed to be lowered over time. But in some cases, immune responses become more than needed which leads to the deadly local and systemic inflammatory response.
During innate immunity response, Pattern recognition receptors (PRRs) located on macrophages and antigen-presenting cells such as dendrites recognize and bind with different pathogen-associated molecular patterns (PAMPs). Binding of PAMPs to PRPs activate several signaling pathways and induce transcription of various genes e.g genes encoding pro-inflammatory cytokines, chemokines, and adhesion molecules. These series of events result in the appearance of leukocyte and plasma protein at the site of infection to combat invaded pathogens. This is a normal immune response but the exaggerated immune response can worsen the infection. In patients of COVID- 19, overactive immunity results in cytokine storm due to an increased level of circulating pro-inflammatory compounds. The important pro-inflammatory cytokines are IL-1, IL-6, and TNF-α. The increase in cytokine number results in increases in the number of immune cells such as leukocytes at the site of infection which has injurious effects on host cells as immune cells infiltrate and damage the lung tissues. Further, cytokine storm can also cause blood vessel leakiness, blood clotting inside the body, lack of oxygen, multi-system organ dysfunction build-up of fluid in lungs which ultimately leads to Acute Respiratory Distress Syndrome (ARDS) which if left untreated can cause death.
From the above discussion, it is obvious that we need not only antiviral therapy but anti-inflammatory drugs as well for the treatment of severely ill SARS-COV 2 patients. Dexamethasone is the first drug to show reduced mortality rate in COVID 19 patients. On June 16, RECOVERY trial results from the united kingdom show that Dexamethasone reduced deaths by one-third in ventilated patients and by one fifth in other patients receiving oxygen only. There was no benefit among those patients who did not require respiratory support
Dexamethasone biochemical actions overlap with COVID-19 pathology as it limits the production of cytokines and macrophages.
Contraindications and cautions
Dexamethasone should not be used in the following conditions:
· Fungal infections
· Systemic infections
· Cerebral malaria
· Hypersensitivity to dexamethasone
· Glaucoma
· Diabetes mellitus
· Depression/ Mental disorders
· Hypertension
· Hypothyroidism
· Ulcerative colitis
· Epilepsy
· Myasthenia gravis
· Congestive heart failure
Adverse reactions
· Adrenal suppression
· Glaucoma
· Heart failure
· Hypertension
· Disturbed metabolism
· Diabetes
· Cataracts
· Increased susceptibility to infection
· Headache and Dizziness
Drug-DRUG interaction
· When taken with NSAIDs, the risk of peptic ulceration and bleeding increases.
· It can develop hyperkalemia if administered along with Amphotericin B injection and potassium-depleting agents.
· Aminoglutethimide is an adrenal steroid inhibitor.
· If combined with Aceclofenac, the risk of gastrointestinal irritation increases.
REFERENCES:
https://www.cebm.net/covid-19/dexamethasone/
https://www.biolifesas.org/biolife/2020/06/19/dexamethasone-for-covid-19-not-so-fast/
https://www.sciencedirect.com/science/article/pii/S187140212030223X
